Abstract
Purpose :
APX3330 is a small molecule inhibitor of Ref-1, a target involved in key vascular and inflammatory ocular disease processes including diabetic retinopathy (DR), diabetic macular edema (DME) and wetAMD. The purpose was to determine the efficacy of oral administration of APX3330 to reduce lesion size in a laser-induced choroidal neovascularization (L-CNV) mouse model and to develop a physiological-based pharmacokinetic (PBPK) model for retinal delivery of APX3330 to confirm dosing for a Phase 2 trial.
Methods :
Following laser treatment, mice received twice daily gavages of 25 or 50 mg/kg APX3330 or vehicle for 14 days. Optical coherence tomography (OCT), fundoscopy, and 3-dimensional quantification of agglutinin stained CNV were performed. The Ocular Compartmental Absorption and Transit (OCAT™) model within GastroPlus 9.6 was used to build a mechanistic compartmental model accounting for APX3330 systemic absorption and retinal distribution in the human eye. ADMET Predictor™ 9.5 was used to model systemic distribution and clearance using physicochemical and biopharmaceutical properties. PBPK simulation results for single oral doses of APX3330 (60, 180, and 240 mg) were compared to plasma concentrations observed in multiple Phase 1 clinical trials. Simulations for retinal exposure using 480 and 600 mg total daily doses across different dosing regimens were also performed.
Results :
At both 25 and 50 mg/kg doses, APX3330 reduced size of L-CNV lesions by >50%. No obvious signs of ocular toxicity were observed during treatment. PBPK model predictions matched reported human plasma concentrations of APX3330 after oral administration and demonstrated predictive capability of the developed model. Predicted retinal exposures were 13.5; 12.3; 15.4; 16.5 and 20.7 ug*h/mL after 200 mg TID, 240 mg BID, 300 mg BID, 480 mg QD and 600 mg QD, respectively.
Conclusions :
Oral administration of APX3330 safely and effectively reduced neovascularization in an L-CNV preclinical model. The PBPK model resulted in important insights into delivery of orally administered APX3330 to the human retina with predicted human retina levels significantly higher than observed and required for efficacy in preclinical studies. These findings confirm the 600 mg dose BID for APX3330 in a planned DR/DME Phase 2 trial.
This is a 2021 ARVO Annual Meeting abstract.